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Obesity, and corresponding chronic‐low grade inflammation, is associated with the onset and progression of knee OA. The origin of this inflammation is poorly understood. Here, the effect of high fat, high sucrose (HFS) diet induced obesity (DIO) on local (synovial fluid), and systemic (serum) inflammation is evaluated after a 12‐week obesity induction and a further 16‐week adaptation period. For 12‐weeks of obesity induction, n = 40 DIO male Sprague–Dawley rats consumed a HFS diet while the control group (n = 14) remained on chow. DIO rats were allocated to prone (DIO‐P, top 33% based on weight change) or resistant (DIO‐R, bottom 33%) groups at 12‐weeks. Animals were euthanized at 12‐ and after an additional 16‐weeks on diet (28‐weeks). At sacrifice, body composition and knee joints were collected and assessed. Synovial fluid and sera were profiled using cytokine array analysis. At 12‐weeks …